Recognizing and understanding where and when events occurred is essential for normal learning and memory of life experiences. Disruptions in the normal processing of spatial and episodic memories can have devastating consequences; in particular this is one component of the debilitating cognitive deficits of schizophrenia (SCZ). While much is known about the clinical symptoms and we are beginning to understand the molecular changes in SCZ, very little is known about the neural circuit disruptions and how they lead to behavioral and cognitive dysfunction. Our goal is to investigate neural circuit dysfunctions in SCZ in order to better understand the severe cognitive deficits underlying the disease. In particular, deficits in spatial and episodic memory are two of the primary cognitive dysfunctions in SCZ; cognitive functions that have been linked unequivocally to the hippocampus (HPC), which has been independently implicated in SCZ pathology, but how individual hippocampal circuit elements are disrupted remains unknown. This proposal uses recent advances in neuroscience tools to probe neural circuits in ways not previously possible. It will make use of recent progress in understanding the genetic factors leading to schizophrenia by studying the etiologically-validated Df(16)A deletion mouse model of the human 22q11.2 deletion syndrome mutation which is highly associated with schizophrenia. This project will test the hypothesis that hippocampal area CA1 principal neurons are disrupted during spatial navigation and goal-directed spatial learning in the schizophrenia mouse model by using two-photon imaging of genetically-encoded calcium- indicators in awake head-fixed mice to record the response of populations of hundreds of pyramidal cells during these behaviors. Preliminary data suggests that spatial representations are more rigid, they don't as readily adapt over time. It is known that spatial memory can be robustly modulated by novelty, salience, and attention, all of which are signaled by neuromodulatory inputs to the hippocampus. The proposed research will test the hypothesis that disrupted stability in a schizophrenia mouse model is caused by altered dopaminergic or cholinergic activity, by using a combination of awake in vivo activity imaging and optogenetic manipulations. Taken together, this proposed research will use head-fixed two-photon function imaging of awake schizophrenia-mutant mice in order to directly probe hippocampal circuit dysfunctions linked to cognitive deficits in schizophrenia, potentially elucidating novel targets for treatment.